Deafness and hearing loss due to damage of the inner ear and cochlear nerve remain as the major incurable otological disorders today, despite recent advances with cochlear prostheses. Less common, but of much concern are congenital forms of damage, since the resulting hearing impairment profoundly disturbs the development of communication skills. The goal of the present proposal is to elucidate the mechanisms controlling the assembly of the sensorineural structures of the inner ear and the connections with the central auditory pathways. The approach uses in vitro methods to analyze the role of sensorineural interactions in the development of these auditory structures. Cell cultures of defined tissue explants from the anlagen of the ear and acoustic nuclei of chicken or mouse embryos are used to determine the cell types involved in these interactions. The aim is to identify the specific cell types that interact during neurogenesis of the cochlear ganglion and nucleus and to characterize the cellular interactions occurring in vitro. Experiments are designed to reveal factors involved in these interactions and the loci of their actions at the molecular level. Antibodies and in situ hybridization will be used for localizing such molecules to specific cell types at the critical stages and to perturb the developmental process in situ. Experimental transplantation of cultured mouse cochlear ganglion neuroblasts will be carried out to evaluate their interactions with the cochlear nucleus and inner ear of neonatal and adult animals. Ultimately these findings should provide a rational basis for developing transplantation therapies.